Sleep disordered breathing (SDB) is a major health problem affecting an estimated 18 million people in the USA alone. Clinical manifestations of SDB include obstructive sleep apnea (OSA), central apnea and periodic breathing. While treatment options for central apnea and periodic breathing are limited, continuous positive airway pressure (CPAP) is the current choice of treatment for OSA. However, substantial populations of OSA patients are refractory to CPAP treatment. Consequently, there is an absolute need for developing alternative and adjunctive strategies for treating SDB. A heightened carotid body chemo reflex plays a substantial role in SDB pathophysiology - both as mediator of the disease and the downstream pathology caused by intermittent hypoxia. Thus, preventing carotid body hypersensitivity is a potential therapeutic intervention for treating SDB and its effects. Our recent studies suggest that enhanced --lyase (CSE) catalyzed hydrogen sulfide (H2S) generation contributes to carotid body hypersensitivity and L-propargylglycine (L-PAG), an inhibitor of CSE enzyme reduces carotid body hypersensitivity and normalizes breathing in rodent models of SDB. Based on these findings the current proposal seeks CADET-2 funding to pursue a preclinical development program in which L-PAG is chemically optimized for efficacy, potency, selectivity, safety, and desirable pharmacological and pharmaceutical properties, culminating in a new candidate medicine suitable for treating SDB. AIM 1 proposes to develop highly selective and potent small molecule inhibitors of CSE as drug candidates for SDB. Studies in AIM 2 perform in vivo screening of compounds for their efficacy, potency, and selectivity for on-target effects on breathing with apnea in rodent models. AIM 3 establishes preclinical toxicology, pharmacokinetics and metabolism. AIM 4 will facilitate filing an investigational new drug (IND) application with the US FDA. Successful and safe pharmacological inhibition of hyperactive chemo reflex has the potential to open up an entirely new frontier of medical treatment for alleviating SDB with apneas in CPAP resistant OSA, central apnea and periodic breathing patients. (End of Reviewers' Comments)